The health economic objectives for this assessment were to:
- review and critically appraise published economic evaluations of first-line pre-hospital or ED treatments for adults with status epilepticus, with a focus on the type and structure of decision models used to address the decision problem
- identify the key elements of a suitable economic model for assessing the cost-effectiveness of pre-hospital or ED treatments from the perspective of the UK NHS, based on the review of published economic evaluations and findings from the clinical effectiveness review.
Methods
Search strategies were developed to identify economic evaluations of pre-hospital or first-line ED treatments for adults with status epilepticus (see Appendix 11 for more details). The following databases were searched, with no date, language, or publication type restrictions: MEDLINE, EMBASE, NHS Economic Evaluation Database (NHS EED), Health Technology Assessment (HTA) Database, Research Papers in Economics (RePEc), and the International Society of Pharmacoeconomics and Outcomes Research (ISPOR) Scientific Presentations Database.
Any identified full economic evaluations matching the scope of this assessment were included. Full economic evaluations were defined as comparative analyses of costs and outcomes in the framework of cost–utility, cost-effectiveness, cost–benefit or cost minimisation analyses. Economic evaluations conducted alongside single effectiveness studies (e.g. RCTs) or decision-analysis models were also deemed eligible for inclusion.
The publications identified through the literature search as potentially meeting the scope of the cost-effectiveness assessment were reviewed for eligibility. Publications were screened intially at abstract level, with eligible abstracts undergoing detailed screening at full-text level.
Results
Quantity of the evidence
In total, 103 results were identified through database searching. Abstract screening excluded 96 records, with the main reason for exclusion being the lack of economic evaluation. The remaining seven full-text articles were assessed for eligibility, and six were excluded because of either inappropriate study design (no economic evaluations, n = 3) or patient population (n = 3). Of the three articles excluded because of the lack of economic evaluation, two reported only costs and one was a review of evidence on the use of fosphenytoin. One record matched the inclusion criteria and was included in this review. The PRISMA flow diagram for study selection is provided in Figure 4.
FIGURE 4 The PRISMA flow diagram for the selection of cost-effectiveness evidence. (Figure not reproduced here; see the original article.)
Results of the individual studies
The included study is a retrospective case note audit comparing the efficacy, safety and cost of lorazepam (4 mg i.v., repeated up to two times) compared with diazepam (10 mg i.v., repeated up to three times) in adults with convulsive status epilepticus who received treatment in a teaching hosptial in London.62 Cases of convulsive status epilepticus were retrospectively reviewed over two 18-month periods before and after the introduction of a new management protocol that recommended lorazepam in place of diazepam for first-line treatment of convulsive status epilepticus. Phenobarbitone was also recommended instead of phenytoin for second-line therapy. A total of 720 episodes were identified and 590 medical records were retrieved (82%). These records were examined and 90 episodes of convulsive status epilepticus were identified. Of these, 13 were excluded as no benzodiazepine was received, and a further five were excluded as neither lorazepam nor diazepam was received as part of first-line treatment. The remaining 72 episodes were used to provide a comparison of lorazepam and diazepam. The results of the analysis showed that, when given as the first benzodiazepine, lorazepam was associated with a higher likelihood of treatment success than diazepam (9/17 doses lorazepam vs. 14/55 doses diazepam; p = 0.042). The cost of lorazepam was higher (£0.78 for 4 mg compared with £0.45 for 10 mg) (cost year not specified) but, when used as the first benzodiazepine, lorazepam was significantly more likely to achieve seizure control and patients treated with lorazepam had a lower likelihood of recurrence. The cost per successful outcome was not different between the two treatments (£1.47 for lorazepam vs. £1.46 for diazepam). It was concluded that, where venous access is possible, lorazepam should be the first-line treatment for premonitory and established status epilepticus in place of diazepam in both pre-hospital and in-hospital settings.
A strength of the study is that it is UK based. However, there are some important limitations, notably the retrospective case note design and challenges with note retrieval potentially introducing bias. There were also some differences between the two groups including more patients with premonitory convulsive status epilepticus in the lorazepam group and a shorter time to first treatment, although neither was significant. The number of episodes included in the analysis is also relatively small to draw robust conclusions. The economic analysis presented in the study was a simple cost-effectiveness analysis using the outcome of cost per successful outcome, which was defined as seizure cessation without recurrence over 12 hours. No other outcomes were included in the economic analysis and costs were also limited to first-line medicine acquisition costs with no details provided on the impact on resource use or other medicine costs. Given the narrow focus and limitations identified, it is not possible to draw any robust conclusions on cost-effectiveness.
Other relevant studies
The literature search showed that there is limited evidence available on the cost-effectiveness of first-line pre-hospital or ED treatments for adults with status epilepticus. Given this lack of evidence, other studies (e.g. cost-of-illness studies) were considered with the aim of informing the design of future economic evaluations in this area. With this aim, two costing studies initially excluded during the full-text review were identified in the relevant patient population and these studies were reviewed in detail, as summarised below.
The first study is a retrospective cost-of-illness study that was conducted using data on patients with status epilepticus at three hospitals in Germany.63 The aim of the study was to identify and characterise direct hospital costs (2014 EUR) and cost-driving factors for inpatients with status epilepticus from a German health-care perspective. In total, data from 341 admissions in 316 adult patients between 2013 and 2014 were analysed for costs and cost-driving factors. For each inpatient admission due to status epilepticus, average costs, length of stay and ventilation time were calculated. Patients were categorised according to the aetiology and onset of status epilepticus as follows: acute symptomatic status epilepticus due to acute brain injury (26.3%), new-onset remote symptomatic status epilepticus with no previous history of epilepsy or status epilepticus (28.8%), remote symptomatic status epilepticus with previous history of epilepsy or status epilepticus (38.9%), and other aetiologies (e.g. idiopathic generalised epilepsy) (6.0%). Patients were defined as refractory if they had recurrent seizures despite two appropriately selected and dosed AEDs including benzodiazepine. Super-refractory status epilepticus was defined as status epilepticus that continues or recurs ≥ 24 hours after initiation of treatments with anaesthetic AEDs including cases where seizure control is attained after induction of anaesthesia but recurs on weaning the patient off the anaesthetic agent.
The results of the analysis showed that benzodiazepines were used as first-line treatment in 137 admissions (40.2%) pre-hospital and in 308 admissions (90.3%) prior to AED treatment. Nearly all admissions required the use of electroencephalography (EEG) and cerebral imaging [computerised tomography (CT) and/or magnetic resonance imaging (MRI)]. The mean costs of hospital treatment of status epilepticus were €14,946 per patient per admission with a mean length of stay of 19 days (mean cost per day of €787). Significant cost differences were identified according to the aetiology of status epilepticus, with significantly higher mean costs in patients with acute symptomatic aetiology (€25,269) than in those with new-onset status epilepticus (€12,511), remote symptomatic status epilepticus (€11,204) or status epilepticus of other aetiologies (€10,380). Severity of status epilepticus also had a significant impact on costs, with the largest cost per admission associated with super-refractory status epilepticus (€50,488). Data on length of stay showed that severity was again a significant factor, with durations ranging from 12.1 days in non-refractory patients to 21.0 days in refractory status epilepticus patients and 37.0 days in super-refractory patients.
To identify cost-driving factors, univariate analyses of inpatient treatment costs and length of stay were conducted. This showed increased costs associated with newly diagnosed patients, acute aetiology, unfavourable status epilepticus severity score (STESS) of 4–6 and length of stay of > 14 days. Significantly higher costs and significantly longer hospitalisations were linked to no acute treatment with benzodiazepine before admission, high number of AEDs in hospital, refractory status epilepticus and super-refractory status epilepticus, anaesthesia, requirement for ventilation and unfavourable outcome on discharge (modified Rankin Scale 4–6). Multivariate analysis showed that super-refractory status epilepticus, ventilation and length of stay > 14 days were independent predictors of costs. Limitations of the study include potential lack of generalisability of results to other health-care systems, difficulty in distinguishing costs of status epilepticus from costs due to other acute illnesses (e.g. stroke) and the exclusion of potentially relevant costs, such as rehabilitiation and outpatient costs.
The second study is a retrospective analysis conducted in two hospitals in Spain in which data on patients with status epilepticus were analysed from December 2012 to July 2017.64 The aim of the study was to identify factors that had an impact on the high cost of care in patients with status epilepticus, with focus on the timing of treatment and duration of status epilepticus. Data on seizure history were recorded, as well as whether the status epilepticus episode occurred out of hospital (64%) or in hospital (36%). Aetiology of status epilepticus was categorised into acute symptomatic (55.1%), remote symptomatic (36.4%), progressive symptomatic (7.9%) and cryptogenic (9.5%). The severity of status epilepticus was also evaluated using the modified STESS. Data were collected on the time from onset of status epilepticus to arrival at hospital, time to administration of first-line treatment, time to second-line treatment received (AEDs) and the number of AEDs used, and time to third-line treatment (anaesthetics). Length of stay data were also collected. Duration of status epilepticus was defined as the recorded time from symptom onset until EEG showed a seizure suppression pattern following treatments.
In total, 305 patients were included in the analysis that showed several factors influencing the cost of treatment. These include no previous history of epilepsy, lower level of consciousnessness, the presence of a potentially fatal aetiology, major complications, the presence of lateralised periodic discharges in EEG, a higher epidemiology-based mortality score, being refractory or super-refractory, and the duration of status epilepticus (all p-values ≤ 0.005). The study found that the cost of management is higher for patients in whom onset of status epilepticus occurs in the hospital, rather than out of hospital, meaning that the results for these groups were analysed separately. The total mean cost of in-hospital status epilepticus was €15,174, compared with €6559 for out-of-hospital status epilepticus (p < 0.001) (cost year not specified). Patients in the in-hospital group tended to have more severe status epilepticus symptoms, greater comorbidity, a higher proportion of super-refractory status epilepticus and a higher risk of complications, which together result in an increased length of stay and higher associated costs. The results also showed that the cost of out-of-hospital onset of status epilepticus is higher when the duration of the episode is > 24 hours. In the out-of-hospital group, the duration of the status epilepticus episode was a key factor in the length of hospitalisation and the cost of disease management, with the analysis showing a clear relationship between duration of episode and the time to treatment. For episodes lasting < 24 hours the median cost was €5005, compared with €8733 for episodes lasting ≥ 24 hours (p = 0.005). The authors concluded that the speed at which treatment is initiated is an important factor; therefore, early detection and prompt establishment of treatment could have an impact on both patients’ outcomes and health-care costs. However, there are some limitations with the study, including the retrospective design, meaning that it is difficult to distinguish between costs due to status epilepticus and those associated with other conditions.
Discussion
Limited evidence on the cost-effectiveness of first-line treatments for status epilepticus was identified within the scope of the review. A single retrospective case note audit reporting a cost per successful outcome was the only study meeting the inclusion criteria for the review. This showed that lorazepam was significantly more likely to achieve seizure control and patients treated with lorazepam had a lower likelihood of recurrence, but there was no difference between lorazepam and diazepam in terms of the cost per successful outcome. Owing to limitations with the study, it is not possible to draw firm conclusions. Clinical guidelines show that there is clinical evidence to support benzodiazepines for first-line treatment for convulsive status epilepticus, for which the usual treatments are lorazepam, diazepam and midazolam. As these treatments are associated with broadly similar efficacy in terms of seizure cessation and the cost of treatment is very low (< £1 per dose), they are likely to be considered cost-effective at conventional cost-effectiveness thresholds. However, further research is needed to show which is more cost-effective and which mode of administration is preferable.
When comparing treatments with similar low costs, it is plausible that the more effective treatment will dominate less effective treatments over the course of a treatment episode if it can be shown to lower costs by reducing length of stay in hospital, as is suggested in some of the observational studies. This would preclude the need to estimate quality-adjusted life-years (QALYs) in this scenario. However, from the evidence identified it is clear that, although status epilepticus is an acute condition requiring rapid emergency treatment, to fully assess the cost-effectiveness of status epilepticus treatments an economic model should aim to capture all relevant costs and outcomes associated with the whole episode of status epilepticus. In the event that any higher-cost first-line treatments were to become available in the future, an economic model using the outcome of cost per QALY would be preferable; however, acknowledging the acute nature of status epilepticus may provide some challenges in assessing patients’ quality of life. This approach would allow for the value of higher-cost treatments to be assessed where short-term cost-savings driven by reductions in length of hospital stay are not sufficient to fully offset increased medicine acquisition costs. In addition, the model should aim to capture the potential impact of more effective treatments on reducing longer term health-related quality-of-life loss and account for the recurrent nature of the condition for some patients.
The two costing studies described above provide an indication of the key resource use implications associated with status epilepticus and showed that time to effective first-line treatment of benzodiazepine is key in determining the duration of the status epilepticus episode, the clinical outcomes from treatment, the duration of length of stay and associated treatment costs. In terms of relevant clinical outcomes for inclusion in the economic model, based on the clinical effectiveness review the key clinical outcomes relevant to the economic analysis include cessation of seizure activity, time to seizure cessation, recurrence of seizures, length of stay and ICU admissions. Evidence considered also suggests that different subgroups of status epilepticus have different episode costs, which may warrant further consideration in any future economic evaluation. The costs and quality-of-life loss due to AEs associated with treatment should also be captured, as highlighted by the occurrence of respiratory depression in the included clinical studies. Longer-term complications associated with status epilepticus should also be considered to capture all relevant costs and outcomes. Both costing studies also collected resource use data for patients requiring EEG, CT/MRI scans, AED treatments and requirements for ventilation and anaesthesia.
Summary of cost-effectiveness
Overall, there is a lack of robust data from which to draw firm conclusions on the cost-effectiveness of first-line treatments for status epilepticus, suggesting that further research is required to address this. Evidence from the reviewed costing studies showed the potential for good pre-hospital care to improve clinical outcomes and significantly reduce the burden of hospital resource use.